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The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain

Published online by Cambridge University Press:  26 February 2007

Annemarie Ledeboer ,
Tongyao Liu ,
Jennifer A. Shumilla ,
John H. Mahoney ,
Sharmila Vijay ,
Matthew I. Gross ,
Joseph A. Vargas ,
Lance Sultzbaugh ,
Mark D. Claypool  and
Laura M. Sanftner
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Annemarie Ledeboer*
Affiliation:
Department of Preclinical Development, Avigen Inc., Alameda, CA, USA Department of Psychology and The Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
Tongyao Liu
Affiliation:
Department of Preclinical Development, Avigen Inc., Alameda, CA, USA
Jennifer A. Shumilla
Affiliation:
Department of Preclinical Development, Avigen Inc., Alameda, CA, USA
John H. Mahoney
Affiliation:
Department of Psychology and The Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
Sharmila Vijay
Affiliation:
Department of Preclinical Development, Avigen Inc., Alameda, CA, USA
Matthew I. Gross
Affiliation:
Department of Preclinical Development, Avigen Inc., Alameda, CA, USA
Joseph A. Vargas
Affiliation:
Department of Preclinical Development, Avigen Inc., Alameda, CA, USA
Lance Sultzbaugh
Affiliation:
Department of Preclinical Development, Avigen Inc., Alameda, CA, USA
Mark D. Claypool
Affiliation:
Department of Preclinical Development, Avigen Inc., Alameda, CA, USA
Laura M. Sanftner
Affiliation:
Department of Preclinical Development, Avigen Inc., Alameda, CA, USA
Linda R. Watkins
Affiliation:
Department of Psychology and The Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
Kirk W. Johnson
Affiliation:
Department of Preclinical Development, Avigen Inc., Alameda, CA, USA
*
Correspondence should be addressed to Annemarie Ledeboer, Avigen Inc., 1301 Harbor Bay Parkway, Alameda, CA 94502, USA phone: +1 510 748 7104 fax: +1 510 748 7370 email: [email protected]
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Abstract

Controlling neuropathic pain is an unmet medical need and we set out to identify new therapeutic candidates. AV411 (ibudilast) is a relatively nonselective phosphodiesterase inhibitor that also suppresses glial-cell activation and can partition into the CNS. Recent data strongly implicate activated glial cells in the spinal cord in the development and maintenance of neuropathic pain. We hypothesized that AV411 might be effective in the treatment of neuropathic pain and, hence, tested whether it attenuates the mechanical allodynia induced in rats by chronic constriction injury (CCI) of the sciatic nerve, spinal nerve ligation (SNL) and the chemotherapeutic paclitaxel (Taxol¯). Twice-daily systemic administration of AV411 for multiple days resulted in a sustained attenuation of CCI-induced allodynia. Reversal of allodynia was of similar magnitude to that observed with gabapentin and enhanced efficacy was observed in combination. We further show that multi-day AV411 reduces SNL-induced allodynia, and reverses and prevents paclitaxel-induced allodynia. Also, AV411 cotreatment attenuates tolerance to morphine in nerve-injured rats. Safety pharmacology, pharmacokinetic and initial mechanistic analyses were also performed. Overall, the results indicate that AV411 is effective in diverse models of neuropathic pain and support further exploration of its potential as a therapeutic agent for the treatment of neuropathic pain.

Keywords

ibudilastmechanical allodynianerve injuryspinal cordglia
Type
Research Article
Information
Neuron Glia Biology , Volume 2 , Issue 4 , November 2006 , pp. 279 - 291
Copyright
Copyright © Cambridge University Press 2007

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